Sustained release aminopyridine composition

ABSTRACT

A pharmaceutical composition which comprises therapeutically effective amount of a aminopyridine dispersed in a release matrix, including, for example, a composition that can be formulated into a stable, sustained-release oral dosage formulation, such as a tablet which provides, upon administration to a patient, a therapeutically effective plasma level of the aminopyridine for a period of at least 12 hours, preferably 24 hour or more and the use of the composition to treat various neurological diseases.

CROSS REFERENCES

This application relates to U.S. Provisional Application Ser. No.60/528,760, filed Dec. 11, 2003, U.S. Provisional Application No.60/560,894 filed Apr. 9, 2004, U.S. Provisional Application No.60/528,592 filed Dec. 11, 2003, 60/528,593 filed Dec. 11, 2003, andPCT/US2004/008101 filed on Mar. 17, 2004, all of which are incorporatedherein by reference in their entirety.

BACKGROUND

This invention relates to a sustained release oral dosage form of anaminopyridine pharmaceutical composition that can be used to treatindividuals affected with neurological disorders wherein saidpharmaceutical composition maximizes the therapeutic effect, whileminimizing adverse side effects.

The sustained release oral dosage form of the present invention may beutilized to treat neurological disorders such as spinal cord injuries,multiple sclerosis, Alzheimer's disease, and ALS. Spinal cord injuriesam one of the leading causes of disability in young adults resulting infrom partial to complete paralysis of the lower extremities to partialto complete paralysis from the level of spinal injury downward. In themost extreme cases, paralysis is complete from the C-1 cervical vertebradownward. Oftentimes, however, the injury to the spinal cord does notconsist of an actual severing of the cord but rather consists of aninjury that interferes with signal transmission. Treatment alternativesfor promoting transmission along injured nerves of the spinal cord havethus far met with limited success.

Multiple sclerosis (MS) is a degenerative and inflammatory neurologicaldisease which affects the central nervous system, more specifically themyelin sheath. The condition of MS involves demyelination of nervefibers resulting in short-circuiting of nerve impulses and thus aslowing or blocking of transmission along the nerve fibers, withassociated disabling symptoms. Treatment alternatives for promotingtransmission along affected nerves have thus far been limited.

Alzheimer's disease is a major cause of dementia in the elderly. It maybe described as a progressive pathological deterioration in personality,memory and intellect consistent with a generalized atrophy ofcorresponding brain centers. The emotional state, behavior, cognitivefunction and thought processes of sufferers am all adversely affected. Aminor degrading in memory which gradually becomes more apparent is thefirst indication of the onset of the disease. Part of the diseaseprocess involves the transmission of nerve signals and, as with MS,treatment alternatives have thus far been limited.

Amyotrophic lateral sclerosis (ALS), commonly referred to as LouGehrig's Disease, is a fatal neuromuscular disease characterized byprogressive muscle weakness resulting in paralysis. ALS patients oftensuffer from symptoms including tripping, stumbling, and falling, loss ofmuscle control and strength in hands and arms, difficulty speaking,swallowing and/or breathing, chronic fatigue, and muscle twitchingand/or cramping. ALS is characterized by both upper and lower motorneuron damage. Symptoms of upper motor neuron damage include stiffness,spasticity, muscle twitching (fasciculations), and muscle shaking(clonus). Symptoms of lower motor neuron damage include muscle weaknessand muscle atrophy.

Potassium channel blockers are a class of compounds that have been foundto improve the conduction of nerve impulses. As a result, they havebecome the focus of attention in the symptomatic treatment of spinalcord injury, MS and Alzheimer's disease. One sub-class of potassiumchannel blockers, aminopyridines have shown promise in the treatment ofneurological diseases. 4-aminopyridine (4-AP), a mono-aminopyridineknown as fampridine, has been found to slow the potassium flow in nerveimpulse transmission and, thereby, shows effectiveness in restoringconduction in blocked and demyelinated nerves.

Potassium channel blockers have also been found to improve mentalfunction in patients with Alzheimer's disease. This effect is believedto be related to the potassium channel blocking action which in turnenhances calcium influx into the neuron thus prolonging nerve actionpotential and increasing transmitter release. Mono- anddi-aminopyridines constitute a particular sub-class of potassium channelblockers that have showed promise in the treatment of Alzheimer'sdisease.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical composition whichcontains one or more potassium channel blockers and which can be used inthe effective treatment of various diseases, for example, spinal cordinjury, multiple sclerosis, Alzheimer's disease, and ALS. Embodiments ofthe present invention are directed to compositions that include a matrixand a potassium channel blocker. The potassium channel blockers mayinclude aminopyridines, for example, 4-aminopyridine,3,4-diaminopyridine and the like. The composition provides forsustained-release of the aminopyridine from the matrix to maintain theefficacious and safe plasma level of an aminopyridine. The aminopyridinedispersed in the matrix is capable of providing, upon administration toa patient, a desired release profile. The composition may be used toestablish in patients in need of such treatment, a therapeuticallyeffective blood plasma level of the aminopyridine for a period of atleast about 6 hours and preferably up to at least 24 hours in thepatient in a twice-daily administration while avoiding peaks and troughsin the relapse of the aminopyridine. The composition may include a mono-or di-aminopyridine, preferably 4-AP or 3,4-DAP or a combinationthereof, homogeneously dispersed in a rate-controlling polymer matrix,preferably including a hydrophilic polymer likehydroxypropylmethylcellulose (HPMC). The composition of the presentinvention may also include one or more additional active ingredientsand/or one or more pharmaceutically acceptable excipients. Thesecompositions can be used to treat various neurological diseases, forexample, spinal cord injury, multiple sclerosis, Alzheimer's disease,and ALS.

Another embodiment of the present invention is a stable pharmaceuticalcomposition which comprises a therapeutically effective amount of anaminopyridine dispersed in a matrix that provides a release profile ofthe aminopyridine to a patient that has a desired C_(max) to C_(τ)ratio. The composition may be used to establish and/or maintain in apatient, a therapeutically effective level of the aminopyridine.Preferably the aminopyridine in the composition is released over time sothat a therapeutically effective level of the aminopyridine in thepatient can be achieved with twice daily dosing of the composition. In amore preferred embodiment, undesirable spikes or peaks in the release ofthe aminopyridine are avoided.

Another embodiment of the present invention is a stable,sustained-release oral dosage formulation of a composition whichincludes an a therapeutically effective amount of a 4-aminopyridinedispersed in a matrix that provides a release profile of 4-aminopyridinein the blood plasma of the patient extending over a period of at least 6hours, preferably at least 8 hours, and more preferably, at least about12 hours. In another embodiment, a stable, sustained-release oral dosageformulation of a composition includes an a therapeutically effectiveamount of a 4-aminopyridine dispersed in a matrix that provides atherapeutically effective blood plasma level of 4-aminopyridine in thepatient extending over about 24 hours.

Preferably, the oral dosage formulation of the composition is amonolithic tablet formed by compression of the pharmaceuticalcomposition of the present invention. In preferred embodiments, the oraldosage formulation includes a compressed tablet of a therapeuticallyeffective amount of 4-aminopyridine dispersed in matrix which includes ahydrophilic polymer such as HPMC_(max) The oral dosage form of thepresent invention may also include one or more pharmaceuticallyacceptable excipients.

The dispersion of 4-aminopyridine throughout the matrix imparts chemicaland physical stability to the composition while providing asustained-release profile. This enhanced dosage stability is mostnotably observed in compositions and dosage forms of the presentinvention having low concentrations of 4-aminopyridine, and stability isachieved while maintaining the desired controlled-release profile.Specifically, the compressed tablet formulation of the present inventionexhibits superior resistance to moisture absorption by ambient humidityand maintains a uniform distribution of the 4-aminopyridine throughoutthe tablet while providing a release profile of 4-aminopyridine thatpermits establishment of a therapeutically effective concentration ofthe potassium channel blocker with once daily or twice daily dosing ofthe formulation. Preferably the therapeutically effective concentrationreleased by the formulation extends over at least 6 hours, preferably atleast 8 hours, and more preferably to at least 12 hours. In addition,the homogeneity of the dosage form renders it amenable to formation bysimple and inexpensive manufacturing processes as compared with themulti-layered structure of prior sustained-release dosage formulations.

The compositions of the present invention may be used in the treatmentof a condition in a patient which includes establishing atherapeutically effective concentration of a potassium channel blockerin the patient in need thereof. The compositions may be used forbuilding up a level and or maintaining a therapeutically effectiveconcentration of an aminopyridine in the patient by twice daily dosing.The dosages of the present compositions can made with a lowerconcentration of the aminopyridine to facilitate restful periods for thepatient during the day. Where desirable, the compositions of the presentinvention may be formulated to avoid large peaks in initial release ofthe aminopyridine. The compositions of the present invention whenadministered to a patient in need thereof provide for the treatment ofneurological diseases that are characterized by a degradation of nerveimpulse transmission. Preferably, the compositions are a stable,sustained-release tablet of a therapeutically effective amount of amono- or di-aminopyridine, dispersed in HPMC such that therapeuticallyeffective blood plasma level of the mono- or di-aminopyridine ismaintained in the patient for a period of at least 6 hours, preferablyat least 8 hours, and more preferably at least about 10-12 hours in aonce or twice daily administration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of mean plasma profiles associated with theadministration to a patient in both fasted and fed states of a tabletform of 4-AP (fampridine) in accordance with the present inventioncompared with the mean plasma profile associated with the administrationof an immediate release formulation of 4-AP in a gelatin capsule.

FIG. 2 is a graph of mean plasma profiles associated with theadministration (fasted state) of a homogeneous dispersion of 4-AP(fampridine) in a matrix in a tablet form of in accordance with thepresent invention compared with the mean plasma profile associated withthe administration of a layered controlled-release capsule and animmediate release capsule formulations of 4-AP.

FIG. 3 is a graph of the mean change in walking sped observed with theadministration of a sustained release 4-AP (fampridine) according to thepresent invention.

FIG. 4 is a graph of the mean change in LEMMT with the administration ofa sustained release 4-AP (fampridine) according to the presentinvention.

FIG. 5 is a graph of the mean change in Ashworth score with theadministration of a sustained release 4-AP (fampridine) according to thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particularmolecules, compositions, methodologies or protocols described, as thesemay vary. It is also to be understood that the terminology used in thedescription is for the purpose of describing the particular versions orembodiments only, and is not intended to limit the scope of the presentinvention which will be limited only by the appended claims.

The terms used herein have meanings recognized and known to those ofskill in the art, however, for convenience and completeness, particularterms and their meanings are set forth below.

It must also be noted that as used herein and in the appended claims,the singular forms “a”, “an”, and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, reference toa “spheroid” is a reference to one or more spheroid and equivalentsthereof known to those skilled in the art, and so forth. Unless definedotherwise, all technical and scientific terms used herein have the samemeanings as commonly understood by one of ordinary skill in the art.Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of embodimentsof the present invention, the preferred methods, devices, and materialsare now described. All publications mentioned herein are incorporated byreference. Nothing herein is to be construed as an admission that theinvention is not entitled to antedate such disclosure by virtue of priorinvention.

“Buccal” refers to the cheek area in the mouth.

“Local administration” means direct administration by a non-systemicroute at or in the vicinity of the site of affliction, disorder, orperceived pain.

The terms “patient” and “subject” mean all animals including humans.Examples of patients or subjects include humans, cows, dogs, cats,goats, sheep, and pigs.

The term “pharmaceutically acceptable salts, esters, amides, andprodrugs” as used herein refers to those carboxylate salts, amino acidaddition salts, esters, amides, and prodrugs of the compounds of thepresent invention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of patients without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe invention.

The term “prodrug” refers to compounds that are rapidly transformed invivo to yield the parent compounds of the above formula, for example, byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated herein by reference.

The term “salts” refers to the relatively non-toxic, inorganic andorganic acid addition salts of compounds of the present invention. Thesesalts can be prepared in situ during the final isolation andpurification of the compounds or by separately reacting the purifiedcompound in its free base form with a suitable organic or inorganic acidand isolating the salt thus formed. Representative salts include thehydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate,oxalate, valerate, oleate, palmitate, stearate, laurate, borate,benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionateand laurylsulphonate salts, and the like. These may include cationsbased on the alkali and alkaline earth metals, such as sodium, lithium,potassium, calcium, magnesium, and the like, as well as non-toxicammonium, tetramethylammonium, tetramethylammonium, methlyamine,dimethlyamine, trimethlyamine, triethlyamine, ethylamine, and the like.(See, for example, S. M. Barge et al., “Pharmaceutical Salts,” J. Pharm.Sci., 1977, 66:1-19 which is incorporated herein by reference.).

“Slow or sustained release formulation” refers to a formulation designedto release a therapeutically effective amount of drug or other activeagent such as a polypeptide or a synthetic compound over an extendedperiod of time, with the result being a reduction in the number oftreatments necessary to achieve the desired therapeutic effect. In thematter of the present invention, a slow release formulation woulddecrease the number of treatments necessary to achieve the desiredeffect in terms of reduction in pain or spasticity, or an improvement inmotor or sensory function in patients in need of such therapy, forexample, in spinal cord injured patients or in patients suffering frommultiple sclerosis, ALS or Alzheimer's disease. The slow or sustainedrelease formulations of the present invention achieve a desiredpharmacokinetic profile in a subject.

“Sublingual delivery” refers to the system delivery of drugs or otheragents through the mucosal membranes lining the floor of the mouth.

A “therapeutically effective amount” is an amount sufficient to decreaseor prevent the symptoms associated with a medical condition or infirmityor to normalize body functions in disease or disorders that result inimpairment of specific bodily functions. As related to the presentapplication, a therapeutically effective amount is an amount sufficientto reduce the pain or spasticity associated with the neurologicaldisorder being treated, or an amount sufficient to result in improvementof sexual, bladder or bowel function in subjects having a neurologicaldisorder which impairs nerve conduction, which hinders normal sexual,bladder or bowl functions.

“Treatment” refers to the administration of medicine or the performanceof medical procedures with respect to a patient, for either prophylaxis(prevention) or to cure the infirmity or malady in the instance wherethe patient is afflicted.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

One aspect of the invention is a sustained-release pharmaceuticalcomposition comprising an aminopyridine dispersed in a sustained releasematrix such as a rate-controlling polymer. The composition of thepresent invention is capable of providing, upon administration to apatient, a release profile of the aminopyridine extending over at least6 hours, preferably least about 12 hour, and more preferably at least 24hours or more. Preferably the aminopyridine concentration in thecomposition is a therapeutically effective amount, and preferably theaminopyridine is dispersed uniformly throughout the release matrix. Atherapeutically effective amount is an amount of a potassium channelblocker, preferably an aminopyridine compound, that when administered toa patient or subject, ameliorates a symptom of a neurological disease.

When the compositions of the present invention are administered to apatient, the concentration of the aminopyridine in the patient's plasmaover time (release profile) may extend over a period of at least 6hours, preferably over at least 8 hours, and more preferably over atabout 12 hours. The compositions may provide in single dose a meanmaximum plasma concentration of aminopyridine in the patient of fromabout 15 to about 180 ng/ml; a mean T_(max) from about 1 to about 6hours, more preferably about 2 to about 5.2 hours after administrationof the composition to the patient.

In one embodiment, aminopyridine is administered to a subject at a doseand for a period sufficient to allow said subject to tolerate said dosewithout showing any adverse effects and thereafter increasing the doseat selected intervals of time until a therapeutic dose is achieved. Inone embodiment the medicament is administered to a subject at a dose andfor a period sufficient to allow said subject to tolerate said dosewithout showing any adverse effects and thereafter increasing the doseof aminopyridine at selected intervals of time until a therapeutic doseis achieved. For example, at the commencement of treatment aminopyridineis preferably administered at a dose less than 15 mg/day until atolerable state is reached. Suitably when said tolerable state isreached, the dose administered may be increased by amounts of at least5-15 mg/day until said therapeutic dose is reached. The method caninclude scheduling administration of doses of the pharmaceutical so thatthe concentration of the aminopyridine in the patient is at about theminimum therapeutically effective level to ameliorate the neurologicalcondition, yet relatively lower compared to the maximum concentration inorder to enhance restful periods for the patient during the day.Preferably the method provides for the treatment of neurologicaldiseases characterized by a degradation of nerve impulse transmissioncomprising the step of administering to a patient a composition of thepresent invention.

The formulations and compositions of the present invention exhibit aspecific, desired release profile which maximizes the therapeutic effectwhile minimizing adverse side effects. The desired release profile maybe described in terms of the maximum plasma concentration of the drug oractive agent (C_(max)) and the plasma concentration of the drug oractive agent at a specific dosing interval (Cτ). A ratio of C_(max) toC_(τ) (C_(max):C_(τ)) may be calculated from the observed C_(max) andC_(τ). A dosing interval (τ) is the time since the last administrationof the drug or active agent. In the present application, the dosinginterval (τ) is twelve (12) hours, therefore C_(τ) is the concentrationof the drug or active agent at twelve (12) hours from the lastadministration.

Additionally, the formulations and compositions of the present inventionexhibit a desired release profile that may be described in terms of themaximum plasma concentration of the drug or active agent at steady state(C_(maxSS)) and the minimum plasma-concentration of the drug or activeagent at steady state (C_(minSS)). Steady state is observed when therate of administration (absorption) is equal to the rate of eliminationof the drug or active agent. A ratio of C_(maxSS) toC_(minSS)(C_(maxSS):C_(minSS)) may be calculated from the observedC_(maxSS) and C_(minSS). In addition, the formulations and compositionsof the present invention exhibit a desired release profile that may bedescribed in terms of the average maximum plasma concentration of thedrug or active agent at steady state (C_(avSS)).

Another embodiment is a sustained release tablet of a sustained releasematrix and an aminopyridine, said tablet exhibits a release profile toobtain a C_(max):C_(τ) ratio in vivo of 1.0 to 3.5, and more preferablya C_(max):C_(τ) ratio of about 1.5 to about 3.0. In another preferredembodiment, the C_(max):C_(τ) ratio is about 2.0 to about 3.0. Theaminopyridine may comprise 4-aminopyridine. The sustained release matrixmay include for example, hydroxypropylmethylcellulose, or other ratecontrolling matrices that are suitable for controlling the release rateof an aminopyridine for use in the pharmaceutical compositions of thepresent invention.

In a further embodiment, a sustained release tablet of a sustainedrelease matrix and an aminopyridine, wherein the tablet exhibits an invivo C_(max):C_(τ) ratio of about 2.0 to about 3.0.

A method of treating a disease associated with a neurological disorderis also provided. The method may include administering an4-aminopyridine on a dosing regimen to obtain an in vivo C_(max):C_(τ)ratio of 1.0 to 3.5. In more preferred embodiments, the C_(max):C_(τ)ratio is about 1.5 to 3.0, and about 2.0 to about 3.0. Such neurologicaldisorders include a spinal cord injury, Alzheimer's disease, multiplesclerosis, ALS or the like. The dosing regimen of the method of treatinga neurological disorder may comprise administering a tablet of saidaminopyridine twice daily dosing. In a further embodiment, thetwice-daily dosing regiment of the aminopyridine may comprise everytwelve hours.

Another embodiment is a method of treating a neurological disordercomprising administering an aminopyridine to achieve an in vivoC_(max):C_(τ) ratio of 1.0 to 3.5, and more preferably the C_(max):C_(τ)ratio is about 1.5 to about 3.25. In another preferred embodiment, theC_(max):C_(τ) ratio of the method of treating a neurological disorder isabout 2.0 to about 3.0.

Another aspect is a therapeutic composition of a release matrix and anactive aminopyridine, wherein the aminopyridine is released from therelease matrix at a rate to maintain a C_(max):C_(τ) ratio of 1.0 to3.5, and more preferably about 1.5 to about 3.0. In another preferredembodiment, the C_(max):C_(τ) ratio of the therapeutic composition isabout 2.0 to about 3.0.

Another embodiment is a sustained release tablet of a sustained releasematrix and an aminopyridine, said tablet exhibits a release profile toobtain a C_(max):C_(τ) ratio in vivo of 1.0 to 3.5 and a C_(avSS) ofabout 15 ng/ml to about 35 ng/ml, and more preferably a C_(max):C_(τ)ratio of about 1.5 to about 3.0. In another preferred embodiment, theC_(max):C_(τ) ratio is about 2.0 to about 3.0.

In another embodiment, a sustained release tablet comprising a sustainedrelease matrix and an aminopyridine, said tablet exhibiting an in vivoC_(max):C_(τ) ratio of about 2.0 to about 3.0 and a C_(avSS) of about 15ng/ml to about 35 ng/ml is provided.

A further embodiment is a method of treating a disease associated with aneurological disorder, said method comprising administering anaminopyridine on a dosing regimen to obtain an in vivo C_(max):C_(τ)ratio of 1.0 to 3.5 and a C_(avSS) of about 15 ng/ml to about 35 ng/ml.

A further aspect is a method of treating a disease associated with aneurological disorder comprising administering an aminopyridine toachieve an in vivo C_(max):C_(τ) ratio of 1.0 to 3.5 and a C_(avSS) ofabout 15 ng/ml to about 35 ng/ml.

In a further aspect, a therapeutic composition comprised of a releasematrix and an active aminopyridine, said aminopyridine being releasedfrom said release matrix at a rate to maintain an in vivo C_(max):C_(τ)ratio of 1.0 to 3.5 and a C_(avss) of about 15 ng/ml to about 35 ng/mlis provided.

In another embodiment, a method of treating a disease associated with aneurological disorder, said method comprising administering anaminopyridine on a dosing regimen to obtain an in vivoC_(maxSS):C_(minSS) ratio of 1.0 to 3.5 and a C_(avss) of about 15 ng/mlto about 35 ng/ml is provided.

A further aspect is a sustained release composition comprising asustained release matrix and an aminopyridine, wherein said compositionprovides a C_(avss) of about 15 ng/ml to about 35 ng/ml. In a furtheraspect, a sustained release tablet comprising a sustained release matrixand an aminopyridine, said tablet exhibiting a C_(maxss) of about 20ng/ml to about 35 ng/ml is provided.

In another embodiment, a sustained release tablet comprising a sustainedrelease matrix and an aminopyridine, said tablet exhibiting a C_(maxss)of about 30 ng/ml to about 55 ng/ml. In a further embodiment, asustained release tablet comprising a sustained release matrix and anaminopyridine, said tablet exhibiting a C_(maxss) of about 24 ng/ml toabout 40 ng/ml is provided. In a further embodiment, a sustained releasetablet comprising sustained release matrix and an aminopyridine, saidtablet exhibiting a C_(maxss) of about 35 ng/ml to about 55 ng/ml isprovided.

A further aspect is a method of treating a disease associated with aneurological disorder comprising administering an aminopyridine on adosing regimen in vivo C_(maxSS):C_(minSS) ratio of 1.0 to 3.5,preferably an in vivo C_(maxSS):C_(minSS) ratio of about 1.5 to about3.0, and more preferably about 2.0 to about 3.0. The dosing regimen mayconsist of administering the aminopyridine twice daily, more preferablyevery twelve hours.

The amount of a pharmaceutically acceptable quality aminopyridine, salt,solvated, or prodrug thereof included in the pharmaceutical compositionof the present invention will vary, depending upon a variety of factors,including, for example, the specific potassium channel blocker used, thedesired dosage level, the type and amount of rate-controlling polymermatrix used, and the presence, types and amounts of additional materialsincluded in the composition. Preferably, the aminopyridine comprisesfrom about 0.1 to about 13% w/w, more preferably from about 0.5 to about6.25% w/w. In an even more preferable embodiment of the presentinvention the aminopyridine is present from about 0.5 to 4.75% w/w ofthe pharmaceutical composition. It has been found that for manyindications a weight (wt/wt %) above about 5% can result in undesirableside effects. Accordingly, a weight percentage less than about 4.75% isdesired. The amount of aminopyridine, or a derivative thereof, in theformulation varies depending on the desired dose for efficient drugdelivery, the molecular weight, and the activity of the compound. Theactual amount of the used drug can depend on the patient's age, weight,sex, medical condition, disease or any other medical criteria. Theactual drug amount is determined according to intended medical use bytechniques known in the art. The pharmaceutical dosage formulatedaccording to the invention may be administered once or more times perday, preferably two or fewer times per day as determined by theattending physician.

Typically, the 4-aminopyridine is formulated in tablets or otherpharmaceutical composition in amounts of about 0.5 mg to about 80 mg,preferably from about 5 to about 50 mg of 4-aminopyridine. Preferably,the amount of an aminopyridine in the composition is formulated tomaintain therapeutic levels of the aminopyridine in patient's blood upto about 80 ng/ml.

The matrix in which the aminopyridine is homogeneously dispersedprovides a sustained release of the aminopyridine into the plasma of thepatient. Polymeric matrices suitable for controlling the release rate ofaminopyridines for use in the pharmaceutical compositions of the presentinvention include hydrophilic polymers; hydrophobic polymers or mixturesof hydrophilic and/or hydrophobic polymers that are capable of formingsustained-release dosage formulation in combination with anaminopyridine. Such matrices are also capable of preventing degradationand loss of the aminopyridine from the composition. Examples of suitablematrices either alone or in combination include but ae not limited tohydroxyalkylcelluloses, such as hydroxypropylcellulose and HPMC,hydroxyethyl cellulose, alkylcelluloses such as ethycellulose andmethylcellulose, carboxymethylcellulose; sodium carboxymethylcellulose,hydrophilic cellulose derivatives, polyethylene oxide, polyethyleneglycol, polyvinylpyrrolidone; cellulose acetate, cellulose acetatebutyrate, cellulose acetate phthalate, cellulose acetate trimellitate,polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate,hydroxypropylmethyl-cellulose acetate succinate; poly(alkylmethacrylate); and poly(vinyl acetate). Examples of other suitablepolymers include, either alone or in combination, carboxyvinylpolymers,poly(vinyl alcohols), glucans, scleroglucans, mannans, xanthans, and, ingeneral, cellulose, crosslinked polyvinylpyrrolidone, carboxymethylstarch, potassium methacrylate-divinylbenzene copolymer,hydroxypropylcyclodextrin, alpha, beta, gamma cyclodextrin orderivatives and other dextran derivatives, natural gums, seaweedextract, plant exudate, agar, agarose, algin, sodium alginate, potassiumalginate, carrageenan, kappa-carrageenan, lambda-carrageenan, fucoidan,furcellaran, laminarin, hypnea, eucheuma, gum arabic, gum ghatti, gumkaraya, gum tragacanth, guar gum, locust bean gum, okra gum, quincepsyllium, flax seed, arabinogalactin, pectin, scleroglucan, dextran,amylose, amylopectin, dextrin, acacia, karaya, guar, a swellable mixtureof agar and carboxymethyl cellulose, a swellable composition comprisingmethyl cellulose mixed with a sparingly cross-linked agar, a blend ofsodium alginate and locust bean gumpolymers or copolymers derived fromacrylic or methacrylic acid esters, copolymers of acrylic andmethacrylic acid eaters, zein, waxes, shellac and hydrogenated vegetableoils.

In certain embodiments, the matrix is a rate-controlling polymer such asbut not limited to HPMC_(max) HPMC is a hydroxyalkylcellulosecharacterized by a polymeric backbone of cellulose, a naturalcarbohydrate that contains a basic repeating structure of anhydroglucoseunits, and varying ratios of hydroxypropyl and methyl substitution atthe three available substitution positions. The amount of substituentgroups on the anhydroglucose units can be designated by weight percentor by the average number of substituent groups attached to the ring. Forexample, if all three available positions on each unit are substituted,the degree of substitution may be designated as 3 whereas if an averageof two positions on each ring are reacted, the degree of substitution iscorrespondingly designated as 2.

According to one method of manufacture, cellulose fibers are heated witha caustic solution and then treated with methyl chloride and propyleneoxide to produce HPMC_(max) The fibrous reaction product is purified andground to a fine, uniform powder. Especially suitable HPMCs manufacturedaccording to this process are sold under the Methocel K designation,such as Methocel K100 LV, Methocel K15M, Methocl K4M and Methocel K100M,all available from the Dow Chemical Co. Methocel K products aregenerally characterized by a methoxyl degree of substitution of about1.4, a methoxyl percentage of about 22%, a hydroxypropyl molarsubstitution of about 0.2, a hydroxypropyl percentage of about 8%, and aparticle size of 90%<100 mesh. In a preferred embodiment, therate-controlling polymer is HPMC sold under the name Methocel K100 LV.

Interaction between the matrix, excipients or other additives and thepotassium channel blocker through van der Waal forces, hydrogen bonding,coordination, solvation, or complex formation may also be desirable tocontrol the release of the potassium channel blocker from thecomposition and to prevent evaporation and or degradation of thepotassium channel blocker within the composition.

In preferred embodiments, the rate-controlling polymer is HPMC_(max) Insuch embodiments, the HPMC preferably has a viscosity (2 wt % solutionat 20° C.) of about 100 to 100,000 cps, more preferably 100 to 30,000cps. Especially suitable HPMCs are Methocel K types, such as MethocelK100 LV, Methocel K15M, Methocel K4M and Methocel K100M, available fromthe Dow Chemical Co. The hydroxypropylmethylcelluloses used according tothe invention preferably have a molecular weight of about 80,000 toabout 1,150,000, more preferably about 80,000 to about 600,000.Especially suitable is a hydroxypropylmethylcellulose sold under thename Klucel LF available from Aqualon and Nippon Soda Co., which has amolecular weight of 100,000. The poly(ethylene oxide) used according tothe invention preferably has a molecular weight of about 100,000 toabout 7,000,000, more preferably about 900,000 to about 7,000,000. Anespecially suitable poly(ethylene oxide) is sold under the name PolyoxWSR Coagulant available from the Dow Chemical Co., which has a molecularweight of 5,000,000. The ethylcelluloses used according to the inventionpreferably have a viscosity of about 3 to about 110 cps, more preferablyabout 7 to about 100 cps. In particularly preferred embodiments, therate-controlling polymer is the HPMC sold under the name Methocel K100LV.

In another embodiment, the rate-controlling polymer is HPC. HPCs usedaccording to the invention preferably have a viscosity (2 wt % solutionat 20 oC.) of about 10 to 100,000 cps, more preferably 100 to 30,000cps, and a molecular weight of about 80,000 to about 1,150,000, morepreferably about 80,000 to about 600,000. An especially suitable HPC issold under the name Klucel LF available from Aqualon and Nippon Soda Co.which has a molecular weight of about 95,000.

In another embodiment, the rate-controlling polymer release matrix ispoly(ethylene oxide) preferably having a molecular weight of about100,000 to about 7,000,000, more preferably about 900,000 to about7,000,000. An especially suitable poly(ethylene oxide) is sold under thename Polyox WSR Coagulant available from the Dow Chemical Co. which hasa molecular weight of about 5,000,000. Suitable ethylcelluloses that maybe used as the rate-controlling polymer in accordance with the inventionpreferably have a viscosity of about 3 to about 110 cps, more preferablyabout 7 to about 100 cps.

The polymeric matrix of the drug delivery of the invention mayadditionally also contain a hydrophobic polymer. Suitable hydrophobicpolymers are hydrophobic cellulose derivatives, such as ethyl cellulose,fats, such as glycerol palmitostearate, waxes, such as beeswax,glycowax, castrowax, carnaubawax, glycerol monostearate orstearylalcohol, hydrophobic polyacriamide derivatives and hydrophobicmethacrylic acid derivatives.

A hydrophobic polymer may be included as part of a release matrix, inorder to modify the release kinetics. Preferably such a hydrophobicpolymer is used only in a mixture of hydrophilic and hydrophobicpolymers. In such a mixture, the hydrophobic polymer controls the waterpenetration rate into the delivery system. For example, incorporation ofa hydrophobic polymer into the polymer matrix and the ratio ofhydrophilic to hydrophobic polymer thus changes the erosioncharacteristics of the tablet. The hydrophobic polymer shows down thewater penetration into the tablet and thus slows the tablet erosion.

The amount of the release matrix included in the pharmaceuticalcomposition of the present invention will vary depending upon a varietyof factors, including, for example, the specific matrix used, itsmolecular weight, is hydrophilicity, the type and amount of potassiumchannel blocker used, and the presence, types and amounts of additionalmaterials included in the composition. Preferably, the rate-controllingpolymer comprises from about 20 to about 96% w/w, more preferably fromabout 20 to about 70% w/w, of the pharmaceutical composition. It isdesirable that the matrix permit release of the potassium channelblocker in the lower gastrointestinal tract.

In general, when the viscosity grade of the matrix polymer is higher,the release rate of the drug is slower. The size, shape and surface areaof the tablet may also be modified to increase or decrease the releaserate of the aminopyridine from the tablet.

In preferred embodiments, the aminopyridine is milled prior to dispersalin the rate-controlling polymer in order to ensure proper particle sizedistribution. Milling of the aminopyridine may be accomplished by anysuitable means such as, for example, an air jet mill, a micronizer, ahammer mill, a ball mill, a cone mill, or other suitable type of mill.The milling is preferably accomplished so that the particle sizedistributions permit satisfactory dosage content uniformity anddissolution profiles. The particle size distribution may be ±25% of themean particle size use in the formulation. In a preferred embodiment,the aminopyridine is milled so that 90% of the particles are smallerthan about 1.5 mm, more preferably smaller than about 1 mm, and evenmore preferably smaller than about 300 μm; 50% of the particles aresmaller than about 1 mm, more preferably smaller than about 600 μm, andeven more preferably smaller than about 150 μm; and 10% of the particlesare smaller than about 500 μm, more preferably smaller than about 400μm, and even more preferably smaller than about 50 μm.

Suitable screen sizes are from about #10 to about #400 mesh, preferably#24 to #60 mesh. In certain embodiments, milling of the aminopyridinemay involve multiple passes of the material through mesh screens at thesame or different mill blade orientations. In one embodiment, themilling process involves two passes of 4-AP through a #24 mesh screen ina FitzMill® comminutor using two different mill blade orientations.

The aminopyridine, in either milled or un-milled form, is dispersed inthe release matrix to form the pharmaceutical composition such that theaminopyridine is distributed substantially uniformly throughout theentirety of the matrix. The dispersal of aminopyridine throughout thematrix may be accomplished by any method capable of achievingsubstantial homogeneity. Preferred dispersal methods include the use ofblenders, for example, planetary and cross-flow blenders. While blendingtime will vary depending on a variety of factors, including, forexample, the specifics of the aminopyridine and rate-controlling polymerused, substantially uniform distribution is preferably realized withinfrom about 10 to about 55 minutes of blending.

The release matrix aminopyridine formulation is preferably fabricatedinto tablets, capsules or granules for oral use. The rate ofaminopyridine release from the tablets may be controlled by the erosionmechanism of the release matrix from which aminopyridine is released. Ingeneral, for producing a tablet on an industrial scale, the drug andpolymer are granulated alone or in combination. Preferably the releaseof the aminopyridine from the matrix of the pharmaceutical compositionis relatively linear over time. Preferably the matrix provides a releaseprofile that gives a therapeutically effective concentration of theaminopyridine in the plasma of the patient permitting a once per day ortwice per day dosing. Preferably the sustained release aminopyridineformulation for oral administration to patients includes from about0.0001 mole to about 0.0013 mole aminopyridine that provides a meanmaximum plasma concentration of aminopyridine from about 15 to about 180ng/ml, a mean T_(max) of about 2 to about 5 hours after administration,and a mean minimum plasma concentration of from about 10 to 60 ng/ml atabout 8-24 hours after administration.

The formulations of the invention are prepared by procedures known inthe art, such as, for example, by the dry or wet method. The methodselected for manufacturing affects the release characteristics of thefinished tablet. In one method, for example, the tablet is prepared bywet granulation in the presence of either water or an aqueous solutionof the hydrophilic polymer or using other binder as a granulating fluid.In alternative, organic solvent, such as isopropyl alcohol, ethanol andthe like, may be employed with or without water. The drug and polymermay be granulated alone or in combination. Another method forpreparation of the tablet which may be used requires using adrug-polymer dispersion in organic solvents in the presence or absenceof water. Where the aminopyridine or its derivative has very lowsolubility in water it may be advantageous to reduce the particle size,for example, by milling it into fine powder and in this way to controlthe release kinetics of the drug and enhance its solubility.

The hardness of the tablets of the present invention may vary, dependingon a variety of factors, including, for example, the relative amountsand specific types of ingredients used, the tableting equipmentemployed, and the selected processing parameters. The pressure used toprepare the tablets can influence the release profile of theaminopyridine into the patient. The pressure used to prepare the tabletsof the present invention may vary depending upon their surface area andthe amount and particle size of aminopyridine, additive, excipients, orbinders included in the tablet. The degree of hydration and solvation ofthe components in the composition will also be important in determiningthe hard ness of the tablets. Preferably the formed tablets have ahardness in the range of from 80-400 N, and more preferably from 150 to300 N.

Pellets or a combination of pellets in accordance with the invention mayalso be filled into hard or soft gelatin capsules. The pellets includedin the capsule may have different amounts of aminopyridine in thepellets and or different matrices. Various amounts of the pellets may beused to tailor the total amount aminopyridine delivered as well as toalter the release and concentration profile of the aminopyridine in thepatient.

The effects of various matrices, concentrations of aminopyridine, aswell as various excipients and additives to the composition on theconcentration of the channel blocker on the dissolution rate may bemonitored for example using a type H dissolution apparatus according toU.S. Pharmacopoeia XXII, or USP Apparatus II (Paddle Method). Clinicalevaluations may be used to study the effects on plasma levels of variousrelease matrices, concentrations of aminopyridine, as well as variousexcipients and additives. Plasma aminopyridine concentrations may beused to calculate pharmacokinetic data (release profiles) includingapparent absorption and elimination rates, area-under-the curve (AUC),maximum plasma concentration (C_(max)), time to maximum plasmaconcentration (T_(max) absorption half-life (T_(1/2)(abs)), andelimination half-life (T_(1/2)(elim)). Pharmacodynamic effects may beassessed based upon response tests, such as muscle strength improvementor reduction in spascticity for patients with multiple sclerosis orspinal cord injury or other tests as would be known to those skilled inthe art. Plasma aminopyridine concentration in blood plasma or cerebralspinal fluid may be monitored using liquid chromatography/MS/MS assaymethods.

The drug delivery of the invention can utilize any suitable dosage unitform. Specific examples of the delivery system of the invention aetablets, tablets which disintegrate into granules, capsules, sustainedrelease microcapsules, spheroids, or any other means which allow fororal administration. These forms may optionally be coated withpharmaceutically acceptable coating which allows the tablet or capsuleto disintegrates in various portions of the digestive system. Forexample a tablet may have an enteric coating which prevents it fromdissolving until it reaches the more basic environment of the smallintestine.

The dispersion of the aminopyridine throughout the release matriximparts enhanced stability characteristics in the dosage formulation.This enhanced stability is achieved without loss of the desiredsustained-release profile. Preferably the release profile, which may bemeasured by dissolution rate is linear or approximately linear,preferably the release profile is measured by the concentration of theaminopyridine in the plasma in the patient and is such to permit twicedaily (BID) dosing.

The pharmaceutical composition of the present invention can include alsoauxiliary agents or excipients, for example, glidants, dissolutionagents, surfactants, diluents, binders including low temperature meltingbinders, disintegrants and/or lubricants. Dissolution agents increasethe dissolution rate of the aminopyridine from the dosage formulationand can function by increasing the solubility of the aminopyridine.Suitable dissolution agents include, for example, organic acids such ascitric acid, fumaric acid, tartaric acid, succinic acid, ascorbic acid,acetic acid, malic acid, glutaric acid and adipic acid, and may be usedalone or in combination. These agents may also be combined with salts ofthe acids, e.g. sodium citrate with citric acid, in order to produce abuffer system.

Other agents that may alter the pH of the microenvironment ondissolution and establishment of a therapeutically effective plasmaconcentration profile of the aminopyridine include salts of inorganicacids and magnesium hydroxide. Other agents that may be used aresurfactants and other solubilizing materials. Surfactants that aresuitable for use in the pharmaceutical composition of the presentinvention include, for example, sodium lauryl sulphate, polyethyleneseparates, polyethylene sorbitan fatty acid esters, polyoxyethylenecastor oil derivatives, polyoxyethylene alkyl ethers, benzyl benzoate,cetrimide, cetyl alcohol, docusate sodium, glyceryl monooleate, glycerylmonostearate, glyceryl palmitostearate, lecithin, medium chaintriglycerides, monoethanolamine, oleic acid, poloxamers, polyvinylalcohol and sorbitan fatty acid esters.

Diluents that are suitable for use in the pharmaceutical composition ofthe present invention include, for example, pharmaceutically acceptableinert fillers such as microcrystalline cellulose, lactose, sucrose,fructose, glucose dextrose, or other sugars, dibasic calcium phosphate,calcium sulfate, cellulose, ethylcellulose, cellulose derivatives,kaolin, mannitol, lactitol, maltitol, xylitol, sorbitol, or other sugaralcohols, dry starch, saccharides, dextrin, maltodextuin or otherpolysaccharides, inositol or mixtures thereof. The diluent is preferablya water-soluble diluent. Examples of preferred diluents include, forexample: microcrystalline cellulose such as Avicel PH112, Avicel PH101and Avicel PH102 available from FMC Corporation; lactose such as lactosemonohydrate, lactose anhydrous, and Pharmatose DCL 21; dibasic calciumphosphate such as Emcompress available-from Penwest Pharmaceuticals;mannitol; starch; sorbitol; sucrose; and glucose. Diluents are carefullyselected to match the specific composition with attention paid to thecompression properties. The diluent is preferably used in an amount ofabout 10 to about 80% by weight, preferably about 20 to about 50% byweight, of the sustained-release composition.

Glidants are used to improve the flow and compressibility of ingredientsduring processing. Suitable glidants include, for example, colloidalsilicon dioxide, a sub-micron fumed silica that can be prepared by, forexample, vapor-phase hydrolysis of a silicon compound such as silicontetrachloride. Colloidal silicon dioxide is a sub-micron amorphouspowder which is commercially available from a number of sources,including Cabot Corporation (under the tradename Cab-O-Sil); Degussa,Inc. (under the tradename Aerosil); and E.I. DuPont & Co. Colloidalsilicon dioxide is also known as colloidal silica, fumed silica, lightanhydrous silicic acid, silicic anhydride, and silicon dioxide fumed,among others. In one embodiment, the glidant comprises Aerosil 200.

Another agent that may be used is a surfactant, dissolution agent andother solubilizing material. Surfactants that are suitable for use inthe pharmaceutical composition of the present invention include, forexample, sodium lauryl sulphate, polyethylene stearates, polyethylenesorbitan fatty acid esters, polyoxyethylene castor oil derivatives,polyoxyethylene alkyl ethers, benzyl benzoate, cetrimide, cetyl alcohol,docusate sodium, glyceryl monooleate, glyceryl monostearate, glycerylpalmitostearate, lecithin, medium chain triglycerides, monoethanolamine,oleic acid, poloxamers, polyvinyl alcohol and sorbitan fatty acidesters. Dissolution agents increase the dissolution rate of theaminopyridine and function by increasing the solubility of theaminopyridine. Suitable dissolution agents include, for example, organicacids such as citric acid, fumaric acid, tartaric acid, succinic acid,ascorbic acid, acetic acid, malic acid, glutaric acid and adipic acid,which may be used alone or in combination. These agents may also becombined with salts of the acids, e.g. sodium citrate with citric acid,in order to produce a buffer system. Other agents that may be used toalter the pH of the microenvironment on dissolution include salts ofinorganic acids and magnesium hydroxide.

The pellets or granulates may be compressed into tablets using a binderand/or hardening agent commonly employed in tablets such asmicrocrystalline cellulose sold under the Trade Mark “AVICEL” or aco-crystallized powder of highly modified dextrins (3% by weight) andsucrose sold under the Trade Mark “DI-PAC” in such a way that thespecific dissolution rate of the pellets is maintained. Binders that aresuitable for use in the pharmaceutical composition of the presentinvention include, for example, starches, ethyl cellulose,polyvinylpyrrolidone, acacia, guar gum, hydroxyethylcellulose, agar,calcium carrageenan, sodium alginate, gelatin, saccharides (includingglucose, sucrose, dextrose and lactose), molasses, extract of Irishmoss, panwar gum, ghatti gum, mucilage of isapol husk,carboxymethylcellulose, methylcellulose, veegum, larch arbolactan,polyethylene glycols, waxes and mixtures thereof. Suitable lowtemperature melting binders include, for example, polyethylene glycolssuch as PEG 6000, cetostearyl alcohol, cetyl alcohol, polyoxyethylenealkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene stearates, poloxamers, andwaxes.

Disintegrants that are suitable for use in the pharmaceuticalcomposition of the present invention include, for example, starches,sodium starch glycollate, crospovidone, croscarmellose, microcrystallinecellulose, low substituted hydroxypropyl cellulose, pectins, potassiummethacrylate-divinylbenzene copolymer, poly(vinyl alcohol), thylamide,sodium bicarbonate, sodium carbonate, starch derivatives, dextrin, betacyclodextrin, dextrin derivatives, magnesium oxide, clays, bentonite andmixtures thereof.

The active ingredient of the present invention may be mixed withexcipients which are pharmaceutically acceptable and compatible with theactive ingredient and in amounts suitable for use in the therapeuticmethods described herein. Various excipients may be homogeneously mixedwith the aminopyridines of the present invention as would be known tothose skilled in the art. For example, aminopyridines may be mixed orcombined with excipients such as but not limited to microcrystallinecellulose, colloidal silicon dioxide, lactose, starch, sorbitol,cyclodextrin and combinations of these.

Lubricants that are suitable for use in the pharmaceutical compositionof the present invention include agents that act on the flowability ofthe powder to be compressed include but are not limited to silicondioxide such as Aerosil 200, talc; stearic acid, magnesium stearate,calcium stearate, hydrogenated vegetable oils, sodium benzoate, sodiumchloride, leucine carbowax, magnesium lauryl sulfate, and glycerylmonostearate.

To further improve the stability of the aminopyridine in the sustainedrelease composition, an antioxidant compound can be included. Suitableantioxidants include, for example: sodium metabisulfite; tocopherolssuch as α, β, δ-tocopherol esters and α.-tocopherol acetate; ascorbicacid or a pharmaceutically acceptable salt thereof; ascorbyl palmitate;alkyl gallates such as propyl gallate, Tenox PG. Tenox s-1; sulfites ora pharmaceutically acceptable salt thereof; BHA; BHT; andmonothioglycerol.

In another embodiment, the pharmaceutical composition of the presentinvention comprises a rate-controlling polymeric matrix comprising of ahydrogel matrix. For instance, an aminopyridine may be compressed into adosage formulation containing a rate-controlling polymer, such as HPMC,or mixture of polymers which, when wet, will swell to form a hydrogel.The rate of release of the aminopyridine from this dosage formulation issustained both by diffusion from the swollen tablet mass and by erosionof the tablet surface over time. The rate of release of theaminopyridine may be sustained both by the amount of polymer per tabletand by the inherent viscosities of the polymers used.

According to another aspect of the invention, there is provided astable, sustained-release oral dosage formulation which includes aneffective amount a aminopyridine dispersed in a release matrix, andwhich, upon administration to a patient or as part of a therapyregiment, provides a release profile (of therapeutically effective bloodplasma level of the aminopyridine) extending for a period of at least 6hours, preferably at least 12 hours, and more preferably at least 24hours. In another embodiment, the stable, controlled-release oral dosageform provides, upon administration to a patient, a therapeuticallyeffective blood plasma level of the aminopyridine for a period of atleast 6 hours, preferably at least 12 hours, and more preferably atleast 24 hours.

The dosage formulation may assume any form capable of delivering orallyto a patient a therapeutically effective amount of a aminopyridinedispersed in a rate-controlling polymer. Preferably, the dosageformulation comprises a monolithic tablet.

Tablet weight will also vary in accordance with, among other things, theaminopyridine dosage, the type and amount of rate-controlling polymerused, and the presence, types and amounts of additional materials.Assuming 4-aminopyridine dosages of from about 2 mg to about 120 mg;tablet weights can range from about 50 mg to about 1200 mg per tablet,and preferably from 250 to 500 mg, and more preferably about 400 mg.

The dosage formulation of the present invention may comprise also one ormore pharmaceutically acceptable excipients as mentioned above. Inpreferred embodiments, the dosage formulation will comprise diluents anda lubricant in addition to the aminopyridine unit dose and therate-controlling polymer. A particularly preferred diluents ismicrocrystalline cellulose sold under the name Avicel PH101, and aparticularly preferred lubricant is magnesium stearate. When thesematerials are used, the magnesium stearate component preferablycomprises from about 0.2 to about 0.75% w/w of the dosage formulation,and the microcrystalline cellulose along with the rate controllingpolymer and aminopyridine comprises the balance of the formulation. Forexample, a tablet formulation including a aminopyridine x % w/w, arate-controlling polymer y % w/w, and microcrystalline cellulose z %,the magnesium stearate amount would be (100-(x+y+z)) where0.2%≤(100−(x+y+z))≤0.75% w/w. As would be known to those skilled in theart, the amount of an additives such as magnesium stearate may varydepending upon the shear rate used to perform the mixing and the amountof such an additive may be changed without limitation to obtain asatisfactory dissolution rate or plasma level of the aminopyridine.

As used herein, the term “sustained-release” includes the release of aaminopyridine from the dosage formulation at a sustained rate such thata therapeutically beneficial blood level below toxic levels of theaminopyridine is maintained over a period of at least about 12 hours,preferably about 24 hours or more. Preferably, the amount of theaminopyridine in the oral dosage formulations according to embodimentsof the present invention establish a therapeutically useful plasmaconcentration through BID administration of the pharmaceuticalcomposition.

If desired, the dosage formulations of this invention may be coated witha sustained-release polymer layer so as to provide additionalsustained-release properties. Suitable polymers that can be used to formthis sustained release layer include, for example, the release matriceslisted above. As desired, the dosage formulation of the invention can beprovided also with a light-protective and/or cosmetic film coating, forexample, film-formers, pigments, anti-adhesive agents and politicizes.Such a film-former may consist of fast-dissolving constituents, such aslow-viscosity hydroxypropylmethylcelluose, for example, Methocel E5 orD14, or Pharmacoat 606 (Shin-Etsu). The film coating may also containexcipients or enteric coatings customary in film-coating procedures,such as, for example, light-protective pigments, for example, ironoxide, or titanium dioxide, anti-adhesive agents, for example, talc, andalso suitable plasticizers such as, for example, PEG 400, PEG 6000,diethyl phthalate or trietyl citrate.

The compositions of the present invention may be used for the treatmentof neurological diseases characterized by a degradation of nerve impulsetransmission by administering to a patient the oral dosage formulationof the present invention. Preferably, the administration is twice dailydosage of a therapeutically effective amount of an aminopyridine, evenmore preferably, 4-AP dispersed in HPMC_(max) The administration canalso include scheduling administration of doses of the pharmaceutical sothat the concentration of the aminopyridine in the patient is at aboutthe minimum therapeutically effective level to ameliorate theneurological condition, yet relatively lower compared to the maximumconcentration in order to enhance restful periods for the patient duringthe day. The compositions may be administered to a subject at a dose andfor a period sufficient to allow said subject to tolerate said dosewithout showing any adverse effects and thereafter increasing the doseof said active agent in the tablets at selected intervals of time untila therapeutic dose is achieved in the subject. For example, at thecommencement of treatment the active agent is preferably administered ata dose less than 15 mg/day until a tolerable state is reached. The doseadministered may then be increased by amounts of at least 5-15 mg/dayuntil a therapeutic dose is reached. For other diseases the amount ofthe aminopyridine required to reach a therapeutically effective amountfor treatment is described in U.S. Pat. No. 5,952,357 the contents ofwhich are incorporated herein by reference in their entirety.

Compositions of the present invention where the potassium channelblocker is a mono- or di-aminopyridine active agent are particularlysuitable for use in the treatment of a neurological disease which ischaracterized by demyelination of the central nervous system, moreespecially multiple sclerosis. The mono- or di-aminopyridine activeagent n accordance with the invention is also suitable for the treatmentof Alzheimer's disease. Additional features and embodiments of thepresent invention are illustrated by the following non-limitingexamples.

Example 1

This example illustrates preparation of compositions of the presentinvention and their release of an aminopyridine. Tablets in accordancewith the present invention having dosages of 5 mg, 7.5 mg and 12.5 mgrespectively were manufactured at 5 Kg scale. Materials were used in theamounts shown in Table 1.

TABLE 1 % w/w % w/w % w/w Milled 4-AP (#50 mesh) 1.25 1.875 3.125Methocel K100LV 60 60 60 Avicel PH101 38.15 37.525 36.275 Magnesiumstearate 0.2 0.2 0.2 Aerosil 200 0.4 0.4 0.4 Equipment Tablet Press HornNoak equipped with 13 × 8 mm oval tooling press speed 42,000 tablets/hrTablet Weight Range (mg) 386-404 (96.5-101.0%) 388-410 (97.0-102.5%)388-406 (97.0-101.5%) Tablet Hardness Range (N) 200-262 179-292 150-268Tablet Potency - mg/tab. (% LC) 97.1 99.1 100.2 Mean CU (mg/tab.)/% CV5.0 mg/1.0% 7.4 mg/0.7% 12.4 mg/1.1% CU Discrete Samples 5.0 mg/1.2% 7.5mg/1.8%   12.3/1.1% (mg/tab.)/% CV Dissolution (%/hr) Mean (SD) Mean(SD) Mean (SD)  1 28.9 1.1 29.2 1.8 25.9 1.1  2 42.7 1.8 42.1 1.6 40.22.5  3 52.8 1.4 53.0 1.0 49.8 2.1  4 61.4 2.2 61.8 1.5 60.1 2.4  6 75.73.1 75.2 1.6 74.8 2.7 10 95.5 3.3 98.7 1.4 93.2 0.9

Prior to blending, 4-AP was milled through #50 mesh screen using aFitzmill® comminutor. The materials were added into a Gral 25 bowl inthe following order: half Methocel K100 LV, Avicel PH101, Aerosil 200,milled 4-AP and the remaining Methocel K100 LV. The mix was blended for15 minutes at 175 rpm, then the magnesium stearate was added and wasfurther blended for 5 minutes at 100 rpm. Samples were taken from topand bottom positions for blend potency analysis. Weight and hardnesschecks were performed every 15 minutes by the check-master E3049.Discrete tablet samples were taken during the compression process toevaluate intra batch content uniformity.

Example 2

This example illustrates that the pharmacokinetic profile of fampridinein compositions of the present invention is altered by administration ina sustained release tablet matrix compared to immediate release andcontrolled release formulations.

There is a delay in absorption manifested by a lower peak concentration,without any effect on the extent of absorption. When given as a single12.5 mg dose, the peak concentration is approximately two-thirds loweras compared to peak values following administration of the Rformulation; the time to reach peak plasma levels was delayed by about 2hours. FIG. 1 is a graph of mean plasma profiles associated with theadministration to a patient in both fasted and fed states of a tabletform of 4-AP (fampridine) in accordance with the present inventioncompared with the mean plasma profile associated with the administrationof an immediate release (IR) formulation. As with the IR formulation,food delayed the absorption of Fampridine-SR. The absorption offampridine was approximately 50% slower following ingestion of a fattymeal, although due to the flatness of the absorption curve, this may beexaggerated value. Extent of absorption did not differ, as values forCmax and AUC were comparable as summarized in Table 2.

TABLE 2 Pharmacokinetic Parameter Values (Mean ± SD) in Studies UsingFampridine SR, CR, and IR Formulations: Single Dose Studies in HealthyAdult Male Volunteers Fed/ C_(MAX) t_(MAX) AUC (0-∞) Study Number Dose(mg) Fasted (ng/mL) (hours) (ng hr/mL) 0494006 12.5 SR (PD12265) Fed28.7 ± 4.3 5.3 ± 0.8 257.0 ± 62.7 N = 12 Fasted 25.6 ± 3.8 2.8 ± 1.3269.9 ± 44.4 12.5 IR (PD12266) Fasted  79.3 ± 16.3 0.9 ± 0.4 294.2 ±55.6 1194002 12.5 SR (PD12907) Fasted 28.5 ± 4.3 2.9 ± 2.4 285.9 ± 37.8N = 12 12.5 CR (4n806) Fasted 37.7 ± 9.9 3.6 ± 0.9 300.0 ± 53.6 12.5 IR(PS644) Fasted  83.5 ± 23.5 0.79 ± 0.3  274.0 ± 59.2

FIG. 2 is a graph of mean plasma profiles associated with theadministration of a tablet form of 4-AP (fampridine) in accordance withthe present invention compared with the mean plasma profile associatedwith the administration of a sustained-release capsule of the presentinvention and an immediate release capsule.

Example 3

This example details the plasma concentration of different dosagetablets of a aminopyridine in compositions of the present inventionadministered to patients with spinal cord injury. Pharmacokineticresults are presented for the subset of 11 patients who completed alldose levels. Maximal plasma concentrations and AUC values increased withincreasing dose, with a mean C_(max) of 152.0 ng/mL at the highest doseof 120 mg/day. The time of the peak and the plasma eliminationhalf-lives were independent of dose. Mean T_(max) ranged from 2.2 hoursto 3.0 hours. The Tin of fampridine ranged from 5.7 to 6.9 hours. Therewere no apparent differences between males and females. Data from thisstudy are summarized in Table 3.

TABLE 3 Pharmacokinetic Parameter Values (Mean ± SD) Following MultipleOral Doses of Fampridine-SR to 11 Patients with SCI. Fampridine -SRDosage C_(MAX) T_(MAX) AUC₍₀₋₁₂₎ T_(1/2) (mg b.i.d.) (ng/mL) (hours) (nghr/mL) (hours) 25  63.4 ± 11.9 2.2 ± 0.9 475.8 ± 65.5 6.4 ± 1.4 30  83.2± 20.5 2.4 ± 1.4  600.0 ± 128.0 6.7 ± 3.8 35  90.2 ± 14.4 2.4 ± 1.2 660.3 ± 137.7 6.9 ± 3.4 40 103.2 ± 19.4 2.6 ± 1.3  771.5 ± 135.3 6.6 ±2.1 50 145.7 ± 27.9 3.0 ± 1.9 1047.6 ± 258.8 5.8 ± 1.9 60 152.0 ± 25.23.0 ± 2.0 1075.0 ± 163.0 5.7 ± 2.3

Example 4

This example details the pharmacokinetic properties of Fampridine-SR intablets of the present invention administered to patients with multiplesclerosis. Plasma samples were analyzed for fampridine using a validatedLC/MS/MS assay with a sensitivity of 2 ng/mL. Noncompartmentalpharmacokinetic parameter values were calculated using standardmethodology.

This was an open-label, multi-center, dose proportionality study oforally administered fampridine in patients with multiple sclerosis.Single doses of fampridine were to be given in escalating doses (5 mg,10 mg, 15 mg, and 20 mg) with at least a four-day interval betweenadministration of each dose of drug. Safety evaluations were to beperformed during the 24 hour period following administration offampridine and blood samples were to be taken at the following times todetermine pharmacokinetic parameters: hour 0 (pre-dose), hours 1-8, andhours 10, 12, 14, 18, and 24.

Twenty-three subjects received all 4 treatments, and one subjectreceived only 3 treatments; data from all treatments were analyzed.Dose-dependent parameters (e.g., peak plasma concentration andareas-under-the curve) were normalized to a 10 mg dose for among-dosecomparisons. Overall observed time of the peak plasma concentration(mean and its 95% confidence interval) was 3.75 (3.52, 3.98) h, observedpeak plasma fampridine concentration (normalized to a 10 mg dose) was24.12 (23.8, 26.6) ng/ml, area-under-the-concentration-time curve(normalized to a 10 mg dose) was estimated to be 254 (238, 270) ng-h/ml,extrapolated area-under-the-concentration-time curve (normalized to a 10mg dose) was 284 (266, 302) ng-h/ml, terminal rate constant equaled 0.14(0.13, 0.15) h⁻¹, terminal half-life was 5.47 (5.05, 5.89) h andclearance divided by bioavailability (CUF) was equal to 637 (600, 674)ml/min.

Dizziness was the most common treatment-related adverse event. Othertreatment related adverse events included amblyopia, asthenia, headache,and ataxia. Them were clinically significant changes in clinicallaboratory values, ECG parameters, vital signs, physical examinationfindings, or neurological examination findings noted over the course ofthis study.

When the plasma concentrations of fampridine were normalized to the 10.0mg dose levels, there were no significant differences between anypharmacokinetic parameter (AUC, C_(max), t_(1/2)) in the 5-20 mg doserange. Fampridine was well tolerated at the doses used in this study.Dose-normalized (to a 10 mg dose) pharmacokinetic parameter values aresummarized in

TABLE 4 Dose-Normalized (at 10 mg) Pharmacokinetic Parameter Values(Mean ± SEM) Following Single Oral Administration of Fampridine-SR toPatients with MS. C_(MAX)- AUC- Dose norm t_(MAX) norm t_(1/2) Cl/F (mg)(ng/mL) (hours) (ng hr/mL) (hours) (mL/min)  5 26.2 ± 0.6 3.9 ± 0.2244.2 ± 9.4 5.8 ± 0.5 619.8 ± 36.2 (n = 24) 10 25.2 ± 0.7 3.9 ± 0.3252.2 ± 7.8 5.6 ± 0.4 641.4 ± 39.1 (n = 24) 15 24.6 ± 0.7 3.6 ± 0.3263.0 ± 7.4 5.5 ± 0.4 632.4 ± 39.0 (n = 24) 20 24.6 ± 0.8 3.6 ± 0.3255.6 ± 6.9 5.1 ± 0.3 653.9 ± 37.1 (n = 23)

Example 5

This example describes the results of an open-label study to assess thesteady state pharmacokinetics of orally administered fampridine(4-aminopyridine) compositions of the present invention in subjects withMultiple Sclerosis. This study was an open-label multiple dose study ofFampridine-SR intended to assess steady state pharmacokinetics in 20patients with MS who previously completed the study summarized in Table4. Fampridine-SR (40 mg/day) was administered as two 20 mg doses, givenas one morning and one evening dose for 13 consecutive days, with asingle administration of 20 mg on Day 14. Blood samples forpharmacokinetic analysis were collected on Days 1, 7/8, and 14/15 at thefollowing intervals: immediately prior to drug administration(baseline), hourly for the first 8 hours, and 10, 12, and 24 hourspost-dose. Additional blood samples were collected 14, 18, and 20 hourspost-dose on Day 14, and 30 and 36 hours post-dose on Day 15.

Pharmacokinetic parameter estimates following the first dose in thesepatients in this study on Day 1 were comparable to those determined whenthey participated in the study summarized in Table 4. No significantdifference in T_(max) was detected among the four means (Singledose=3.76 h; Day 1=3.78 h; Day 8=3.33 h; Day 15=0.3.25 h). C_(max) andC_(max)/C_(τ) on Days 8 (C_(max)=66.7 ng/ml) and 15 (C_(max)=62.6 ng/ml)were significantly greater than those of the single dose treatment andof Day 1 (C_(max)=48.6 ng/ml), reflecting accumulation of the drug withmultiple dosing.

There was no significant difference among the four occasions with regardto either T or C and no difference in C_(max); C_(max)/C_(τ), CUF orAUC_(0-τ), between Days 8 and 15. Further AUC on Days 8 and 15 did notdiffer significantly from total AUC with single dose treatment.Likewise, the estimates of CLF on Days 8 and 15 and of λ and T_(1/2) Inon Day 15 did not differ significantly from those with single dose.

Steady-state was attained by Day 7/8 as evidence by the lack ofdifferences in C_(max) or AUC between Days 7/8 and 14/15; there was noapparent unexpected accumulation. Likewise, the estimates of Cl/F onDays 7/8 and 14/15 of and of T_(1/2)n on Day 14/15 did not differsignificantly from those given a single dose. On the final day ofdosing, mean C_(max) was 62.6 ng/mL, occurring 3.3 hours post-dose. TheT_(1/2) was 5.8 hours. These values are similar to those observed inpatients with chronic SCI receiving similar doses of this formulation.These results are summarized in Table 5.

TABLE 5 Pharmacokinetic Parameter Values (Mean and 95% CI) FollowingMultiple Oral Doses of Fampridine-SR (40 mg/day) to 20 Patients with MS.Parameter C_(MAX) t_(MAX) AUC₍₀₋₁₂₎ t_(1/2) Cl/F Day (ng/mL) (hours) (nghr/mL) (hours) (mL/min) Day 1 48.6 3.8 NE NE NE (42.0, 55.3) (3.2, 4.3)Day 66.7 3.3 531 NE 700 7/8 (57.5, 76.0) (2.8, 3.9) (452, 610) (557,884) Day 62.6 3.3 499 5.8 703 14/15 (55.7, 69.4) (2.6, 3.9) (446, 552)(5.0, 6.6) (621, 786)

Dizziness was the most common treatment-related adverse event. Othertreatment-related adverse events that occurred included nausea, ataxia,insomnia, and tremor. There were no clinically significant changes inmean clinical laboratory values, vital signs, or physical examinationfindings from baseline to last visit. There were no apparent clinicallysignificant changes in corrected QT intervals or QRS amplitudes afteradministration of fampridine.

Fampridine was well tolerated in subjects with multiple sclerosis whoreceive twice daily doses (20 mg/dose) of fampridine for two weeks. Asignificant increase was observed in C_(max), and C_(max)/C_(τ), on Days8 and 15 relative to those on Day 1 and with single dose treatment,reflecting accumulation of fampridine with multiple dosing. A lack ofsignificant differences in C_(max), C_(max)/C_(τ), CUF or AUC_(0-τ),between Days 8 and 15 suggest that near steady-state is reached by Day8. There was no evidence of significant pharmacokinetics during atwo-week period of multiple dosing with fampridine.

Example 6

This was an open-label, single dose, single-center study of thepharmacokinetics and tolerability of escalating doses of orallyadministered Fampridine-SR in fourteen (14) patients with chronicincomplete SCI.

After fasting overnight, a single oral dose of Fampridine-SR (10, 15,20, or 25 mg) was to be administered. Each patient was to receive eachdose in an ascending fashion. Each dose was to be followed by a 7-daywashout period. A single dose of Fampridine-SR was to be administeredorally on Day 1-10 mg, Day 8-15 mg, Day 15-20 mg and Day 22-25 mg with240 mL of tepid water at approximately the same time on each treatmentday. Patients were to continue their fast for 4 hours after dosing andthen a standard meal was to be served. Blood samples for pharmacokineticanalysis were to be obtained at Hour 0 (immediately preceding study drugadministration) and 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, and 24 hoursafter each dose. A baseline urine sample was to be collected prior todosing and urine was to be collected for 24 hours after administrationof the study drug at the following intervals: 0.1 to 4 hours; 4.1 to 8hours; 8.1 to 12 hours; and 12.1 to 24 hours.

There was no detectable fampridine in any of the pre-dose plasmasamples. By visual inspection of plasma concentration-time curves,concentrations were seen to rise for up to the first 4 hours post-doseand then to decline in a monophasic fashion. In some patients, there wasevidence of a second peak. Peak concentrations increased proportionallywith dose, with mean C_(MAX) of 27.7 ng/mL following a single dose of 10mg and mean C_(MAX) of 67.4 ng/mL following a single dose of 25 mg. Peakconcentrations occurred 3 to4 hours post-dose, regardless of dose level.AUC also increased proportionally with increasing dose. The length ofsampling was adequate since AUC₀₋₂₄ is at least 92% of AUC₀₋₈. The meanT % was independent of dose, approximately 6 hours. Pharmacokineticparameter values by dose are summarized in the Table 6 below.

TABLE 6 Mean (±SD) pharmacokinetic parameters of fampridine-SR followingsingle dose administration Fampridine-SR dose 10 mg 15 mg 20 mg 25 mgParameter n = 14 n = 14 n = 14 n = 13* C_(max) (ng/mL) 27.7 ± 9.1  43.5± 11.2 54.9 ± 11.0 67.4 ± 13.3 t_(max) (h) 3.2 ± 1.0 3.5 ± 1.2 3.5 ± 1.03.7 ± 1.2 AUC_(0-24 h) (ng · h/mL) 285.4 ± 96.8  423.0 ± 98.6  561.1 ±117.6 715.6 ± 150.0 AUC_(0-∞) (ng · h/mL) 311.8 ± 93.2  460.2 ± 100.2604.3 ± 124.6 769.2 ± 154.4 K_(el) (h⁻¹) 0.13 ± 0.03 0.12 ± 0.03 0.12 ±0.02 0.13 ± 0.03 t_(1/2) (h) 5.9 ± 1.5 5.9 ± 1.5 5.9 ± 1.4 5.8 ± 1.6Cl/F (L/h) 34.8 ± 10.2 34.3 ± 8.9  34.7 ± 8.5  34.0 ± 8.3  V_(d)/F (L)299.8 ± 127.4 289.0 ± 93.7  289.9 ± 84.1  286.2 ± 123.2 *One patient wasexcluded from analysis, as not all blood samples were collected.C_(max), maximum observed plasma concentration; t_(max), time to reachC_(max); AUC, area under the plasma concentration-time curve; K_(el),elimination rate constant; t_(1/2), plasma half-life; Cl/F, apparenttotal clearance; V_(d)/F, apparent volume of distribution.

Fampridine pharmacokinetic parameters following the oral administrationof single doses of fampridine-SR (10-25 mg) are summarized in Table 6.Fampridine-SR was slowly absorbed (mean t_(max) occurring 3.2 to 3.7hours postdose) and slowly eliminated in a monophasic manner (meant_(1/2)˜5.9 hours). Mean t_(1/2), K_(el), V_(d)/F, and Cl/F wereindependent of dose over the dose range (10-25 mg), while mean C_(max),AUC_(0-24h), and AUC_(0-∞) were linearly related to dose. AUC_(0-24h)was at least 92% of AUC_(0-∞). Mean C_(max) for the lowest fampridine-SRdose (10 mg) was 27.7 ng/mL, while mean C_(max) for the highest dose (25mg) was 67.4 ng/mL.

The plasma concentration profile following administration ofFampridine-SR was consistent with a sustained release of drug. Peakconcentrations of fampridine occurred on average 3 to 4 hours post-dose,and concentrations declined with a plasma half-life of approximately 6hours. The results of this study indicate that Fampridine-SRpharmacokinetics are linear over the single dose range studied, 10 to 25mg. Area under the curve (AUC) and peak plasma concentration (C_(MAX))increased proportionally with dose.

Fampridine-SR was well-tolerated over the range of single oral dosesadministered in this study. Dizziness was the most frequently reportedadverse event. The next most common events were hypotension, nausea, andparesthesia. There was no clear relationship between dose level andfrequency of adverse events, except with the possibility of nausea,which only occurred at the 25 mg dose. There were no clinicallysignificant changes in vital signs during treatment.

The pharmacokinetic analysis of Fampridine-SR administered once weeklyshowed dose proportionality across single oral doses of 10, 15, 20, and25 mg. Mean peak fampridine concentration increased linearly with dosefrom 27.7 ng/mL following a dose of 10 mg to 69.9 ng/mL following a doseof 25 mg. Absorption was prolonged with peak concentrations occurring onaverage 3 to 4 hours postdose; this was independent of dose. The meanT_(1/2) appeared independent of dose, approximately 6 hours. Single oraldoses of 10, 15, 20, and 25 mg of Fampridine-SR were well-tolerated, asassessed by adverse event reporting, clinical laboratories, vital signmeasurements, physical examinations, and ECG interpretation.

Example 7

This example describes the results of an open-label, multiple dose,single center study to assess the effects of escalating doses of orallyadministered sustained release fampridine (4-aminopyridine) in sixteen(16) patients with chronic incomplete spinal cord injury (SCI).Sustained release tablets of fampridine were administered 10 mg twicedaily for 1 week, 15 mg twice daily for 1 week, 20 mg twice daily for 1week and 25 mg twice daily for 1 week in sixteen patients with SCI.

Following administration of Fampridine-SR, fampridine was slowlyadsorbed, with peak concentration observed approximately three hourspost-dose, regardless of dose (p=0.227). Plasma levels declinedgradually with a half life of 6 to 7 hours, independent of dose. Basedon the mean trough concentrations, steady state was achieved by Day 5.Steady state maximal, minimal, and average plasma concentrations and AUCincreased with increasing dose. Total clearance ranged between 9 and 10mL/min/kg across dose groups. Volume of distribution at steady stateranged from 2.01 L/kg in the 15 mg BID dose group to 2.11 L/kg in the 20mg BID dose group. A summary of the mean pharmacokinetic results isprovided in Table 7.

Fampridine pharmacokinetic parameters following the oral administrationof multiple doses of fampridine-SR (10-25 mg BID) are summarized inTable 7. Mean t_(max) and t_(1/2) were similar to values found in thesingle-dose study (compare to Table 6). Steady state was achieved by Day5 (4 days of fampridine-SR dosing) following twice-daily administrationof fampridine-SR. Mean t_(max), t_(1/2), K_(el), V_(ss)/F, Cl/F, andmean residence time at steady state (MRT_(ss)) were independent ofdosage following the administration of fampridine-SR (10-25 mg BID).Mean plasma concentrations (C_(maxss), C_(avss), and C_(minss)) andAUC_(0-12h) at steady state were linearly related to dose over thedosage range (fampridine-SR 10-25 mg BID). Mean C_(maxss) at steadystate for the lowest fampridine-SR dosage (10 mg BID) was 32.2 ng/mL andwas 87.2 ng/mL for the highest fampridine-SR dosage (25 mg BID).Corresponding C_(minss)values for the lowest and highest dosages were14.0 and 41.3 ng/mL.

TABLE 7 Mean (±SD) pharmacokinetic parameters of fampridine-SR followingmultiple dose administration Fampridine-SR dose 10 mg BID 15 mg BID 20mg BID 25 mg BID Parameter n = 15 n = 15 n = 14 n = 14 C_(maxss) (ng/mL)32.2 ± 8.9  46.7 ± 10.5 60.1 ± 15.0 87.2 ± 29.0 C_(minss) (ng/mL) 14.0 ±4.4  23.5 ± 9.1  27.3 ± 10.0 41.3 ± 15.2 C_(avss) (ng/mL) 20.8 ± 5.7 31.0 ± 7.2  39.4 ± 9.3  53.3 ± 14.5 t_(max) (h) 2.7 ± 1.0 3.2 ± 0.9 3.1± 1.2 2.6 ± 0.9 AUC_(0-12 h) (ng · h/mL) 249.3 ± 68.3  371.8 ± 86.8 472.3 ± 111.8 639.4 ± 173.9 K_(el) (h⁻¹) 0.14 ± 0.05 0.12 ± 0.03 0.13 ±0.04 0.12 ± 0.05 t_(1/2) (h) 5.6 ± 1.8 6.0 ± 1.5 5.8 ± 2.1 7.6 ± 5.5Cl/F (L/h/kg) 9.52 ± 2.85 9.35 ± 2.44 9.79 ± 2.03 9.15 ± 2.35 V_(ss)/F(L/kg) 2.22 ± 0.79 2.01 ± 0.59 2.11 ± 0.51 2.09 ± 0.65 MRT_(ss) (h) 5.18± 0.21 5.18 ± 0.30 5.15 ± 0.35 5.08 ± 0.31 Accumulation factor 1.30 ±0.18 1.34 ± 0.16 1.32 ± 0.22 1.53 ± 0.62 C_(maxss), maximum observedplasma concentration at steady state; C_(minss), minimum observed plasmaconcentration at steady state; C_(avss), average plasma concentration atsteady state; t_(max), time to reach C_(max); AUC, area under the plasmaconcentration-time curve; K_(el), elimination rate constant; t_(1/2),plasma half-life; Cl/F, apparent total clearance; V_(ss)/F, apparentvolume of distribution at steady state; MRT_(ss), mean residence time atsteady state; BID, twice daily.

Adverse events included pain, hypertonia, dizziness, accidental injury,dyspepsia, asthenia, urinary tract infection and euphoria. There was noclear relationship between frequency of adverse events and dose level,however euphoria and dizziness were observed more frequently in the 25mg BID dose level.

Multiple oral doses of 10, 15, 20 and 25 mg BID of Fampridine-SR weregenerally well-tolerated, as assessed by adverse event reporting,clinical laboratories, vital signs, and physical examinations. Thepharmacokinetic analysis of Fampridine-SR showed dose proportionalityacross multiple oral doses of 10, 15, 20, 25 mg BID each administeredfor 1 week. The results demonstrate that fampridine pharmacokinetics arelinear over the dose range studied. Trough values indicated that steadystate had been achieved by Day 5. Fampridine pharmacokinetics aredose-proportional: both AUC and C_(max) at doses of 10, 15, 20, and 25mg BID, each administered over the course of one week, weredose-proportional under both and ANOVA model and a regression powermodel. Neither rate of absorption (as reflected by the time of the peakconcentration) nor the rate of elimination (K_(el)) were dependent ondose.

Example 8

This was a double-blind, placebo-controlled, 20 week, parallel-groupstudy to evaluate safety, tolerability and activity of oralfampridine-SR in subjects with Multiple Sclerosis. The study wasdesigned as follows: a two-week placebo run-in (single blind); atwo-week upward titration (10 mg bid, 15 mg bid or placebo); atwelve-week stable treatment period (placebo, 10 mg bid, 15 mg bid or 20mg bid); a one-week downward titration (10 mg bid, 15 mg bid or placebo)and a two-week post treatment follow-up. A total of 206 patients wereenrolled in the study.

The mean change in walking speed, the walking speed measured per visit,the mean change in LEMMT, the LEMMT per visit, the adverse events andserious adverse events associated with the study were documented.

Results. The trial showed a strong positive trend across all three dosegroups compared to placebo in its primary endpoint, improvement inwalking speed, as measured by a timed 25-foot walk as shown in FIG. 3 .The trial also showed a statistically significant improvement acrossdose groups in its secondary endpoint, the Lower Extremity Manual MuscleTest (LEMMT), as shown in FIG. 4 . These results confirmed observationsin earlier double-blind trials that involved fewer subjects and shortertreatment periods. Because most people with MS experience bothimpairment in walking ability and weakened muscles, the Timed 25 FootWalk is widely-used to assess MS patients' functional status. The LEMMTis a standardized, 5-point manual assessment of strength, applied to legmuscle groups. The study showed a statistically significant differenceacross all doses at up-titration and follow-up for the 25 foot walk. Thestudy also showed a statistically significant improvement in LEMMTacross all doses during stable treatment. The study confirms the safetyprofile of 4-aminopyridine and preferable dosing of 10 to 15 milligramstwice daily.

Fampridine-SR showed a strong positive trend in the improvement ofwalking speed and significantly improved leg muscle strength in peoplewith multiple sclerosis (MS). The drug also showed a reduction of musclespasticity in people with chronic spinal cord injury (SC).

Example 9

This was a group study to evaluate safety, tolerability and activity oforal fampridine-SR in subjects with spinal cord injury (SCI). The studywas designed as follows: a two-week placebo nm-in (single blind); atwo-week upward titration (10 mg bid, 15 mg bid or placebo); atwelve-week stable treatment period (placebo, or 25 mg bid); a two-weekdownward titration (10 mg bid, 15 mg bid) and a two-week post treatmentfollow-up. A total of 204 patients were enrolled in the study, of which166 completed.

The mean change in Ashworth score, the Ashworth score measured pervisit, the mean change in LEMMT, the LEMMT per visit, the adverse eventsand serious adverse events associated with each study were documented.The Ashworth is a validated, 5-point clinician assessment of anindividual's spasticity (the involuntary tension, stiffness orcontraction of muscles.)

Results. The study showed a statistically significant improvement ofAshworth score using FDA-preferred analysis, as shown in FIG. 5 . Thestudy also confirmed the safety profile of 4-aminopyridine.

Although the present invention has been described in considerable detailwith reference to certain preferred embodiments thereof, other versionsare possible. Therefore the spirit and scope of the appended claimsshould not be limited to the description and the preferred versionscontain within this specification.

1.-5. (canceled)
 6. A process for preparing sustained release4-aminopyridine tablets having from 1.25% wt to 3.125% wt %4-aminopyridine consisting essentially of the steps of: (a) milling4-aminopyridine to produce a particle size distribution such that 90% ofthe 4-aminopyridine particles are smaller than 300 μm, 50% of the4-aminopyridine particles are smaller than 150 μm, and 10% of the4-aminopyridine particles are smaller than 50 μm, (b) blending the4-aminopyridine from step (a) with a rate-controlling polymer, a diluentand a glidant, by dry blending said materials for about from 10 to about55 minutes, to form a blend, (c) adding a lubricant to the blend formedin step (b) and blending said materials for a further 5 minutes to forma final blend, (d) compressing the final blend formed in step (c) toform one or more tablets, and (e) coating the one or more tablets fromstep (d) with a cosmetic film coating; wherein the rate-controllingpolymer is hydroxypropylmethylcellulose and is present in an amount of60% wt of said tablet, wherein the diluent is microcrystalline celluloseand is present in an amount of from 38.15% wt to 36.275% wt, dependingon the amount of 4-aminopyridine present, wherein the glidant is silicondioxide and is present in an amount of about 0.4% wt, wherein thelubricant is magnesium stearate and is present in an amount of about0.2% wt; such that, said sustained release 4-aminopyridine tablets havea mean content uniformity of ± about 0.2% target 4-aminopyridine weightper tablet, wherein the 4-aminopyridine is present in an amount of 10 mgper tablet, wherein the tablets have a mean tablet hardness of fromabout 200N to about 262N, and wherein said tablets exhibit the followingdissolution pattern: about 25.9% to about 28.9% drug released in 1 hour,about 40.2% to about 42.7% drug released in 2 hours, about 49.8% toabout 52.8% drug released in 3 hours, about 60.1% to about 61.4% drugreleased in 4 hours, about 74.8% to about 75.7% drug released in 6hours, and about 93.2% to about 95.5% drug released in 10 hours.